Animal models of human disease are critical for translational research aimed at dissecting disease mechanisms and for developing new therapies. The mouse has been invaluable in this effort, but for many diseases this species fails to model the human phenotype. This is particularly evident in the cases of human lung diseases such as cystic fibrosis (CF), alpha-1 antitrypsin (AAT) deficiency, and primary ciliary dyskinesia (PCD). The basis for this species-specificity in disease susceptibility relates to both differences in lung anatomy and cell biology, and the genetic divergence of mice and humans. Recent advances in the field of animal modeling have placed the domestic ferret at the forefront of new genetically pliable species for modeling human diseases. First, we have developed methods for generating knockout, knock-in, and transgenic ferrets that utilize somatic cell nuclear transfer (SCNT). Second, the ferret genome was recently sequenced and is now publically accessible, providing the information needed to interrogate the genetic suitability of the ferret to model a particular disease, generate gene-targeting constructs, and rapidly generate research tools for studies in this species. As proof of concept, cystic fibrosis transmembrane conductance regulator (CFTR) knockout ferrets have been generated and found to model aspects of multi-organ disease (including spontaneous lung infections) seen in CF patients. Additionally, transgenic ferrets that express fCFTR specifically in the gut (under the direction of the FABPi promoter) have been generated and shown to correct the meconium ileus phenotype in newborn CF ferrets. This R24 resource proposal seeks to create a Center that provides services for ferret disease modeling, with a focus on the distribution of CF ferret resources and the creation of new ferret models of lung disease and of other diseases of NHLBI interest. Other focuses of this proposal will be to provide training in the use of ferrets for research, provide services for alternative in vitro and ex vivo airway models, and promote information exchange with the community through a web site that catalogs and distributes tool-box resources of general use for research in the ferret (antibodies, cDNAs, viral vectors, primary airway cells, improved genome annotation files for omics research). Strategic goals of this application will be to expand the number of ferret disease models available to the research community, allow for broad and cost-effective usage of CF ferret models, and build a self-sustaining business model for ongoing function of the Center past the five years of this proposal.